Neurotoxicity, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
neurotoxicity, unspecified adult solid tumor, protocol specific
Brief summary
RATIONALE: Vitamin E may prevent peripheral neuropathy caused by chemotherapy in patients with cancer. It is not yet known whether vitamin E is more effective than a placebo in preventing peripheral neuropathy caused by chemotherapy in patients receiving chemotherapy for cancer. PURPOSE: This randomized phase III trial is studying vitamin E to see how well it works compared with placebo in preventing peripheral neuropathy caused by chemotherapy in patients receiving chemotherapy for cancer.
Detailed description
OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to type of chemotherapy (taxane vs cisplatin vs carboplatin vs oxaliplatin vs combination), age (≤ 50 years vs \> 50 years), and gender. Patients are randomized to 1 of 2 treatment arms. OBJECTIVES: Primary * Compare the incidence of chemotherapy-induced sensory peripheral neuropathy ≥ grade 2 in patients undergoing curative neurotoxic chemotherapy for cancer treated with vitamin E vs placebo. Secondary * Compare the proportion of patients requiring dose reductions of chemotherapy secondary to sensory peripheral neuropathy. * Compare the proportion of patients stopping chemotherapy before treatment is complete secondary to sensory peripheral neuropathy. * Assess the toxicity of vitamin E in these patients. After completion of study treatment, patients are followed at 6 months.
Interventions
DIETARY_SUPPLEMENTvitamin E
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Required Characteristics: 1. Scheduled to undergo curative-intent adjuvant treatment with neurotoxic chemotherapy. Patients must have had his/her tumor removed, but may have microscopic residual disease, or residual margin involvement and still be eligible. The patient's chemotherapy regimen must include one or more of the following neurotoxic chemotherapeutic agents: taxanes (paclitaxel, docetaxel); platinum compounds (cisplatin, carboplatin, oxaliplatin)-(oxaliplatin patients should preferentially be enrolled in protocol N04C7 while it is available). 2. ≥ 18 years of age 3. Ability to sign informed consent and understand the nature of a placebo-controlled trial 4. ECOG Performance Status (PS) of 0, 1, or 2 e.g. 5. Ability to complete questionnaire(s) by themselves or with assistance 6. Life expectancy ≥ 6 months Contraindications: 1. Undergoing chemotherapy for palliative care 2. Pre-existing history of peripheral neuropathy due to any cause (diabetes, alcohol, toxin, hereditary, etc). 3. Prior treatment with neurotoxic chemotherapy (exception: Patient started neurotoxic chemotherapy ≤ 4 days of starting vitamin E on this study and has not been treated previously with other neurotoxic chemotherapy agents). 4. Taking regular opioid-containing medications. (Exception: opioids, given for the short term treatment of chemotherapy-induced myalgias or arthralgias caused by taxanes are permitted.) 5. Concurrent treatment with anticonvulsants, tricyclic antidepressants, or other neuropathic pain medications agents such as carbamazepine, phenytoin, valproic acid, gabapentin, lamotrigine, topical lidocaine patch, capsaicin cream, etc. 6. History of coronary artery disease (i.e. MI, PTCA, or CABG ≤ 5 years or diagnosis of congestive heart failure of any NY heart class I-IV) Valve replacements are permitted as long as patient has fully recovered from the surgery. 7. Other medical conditions, which in the opinion of the treating physician/allied health professional would make this protocol unreasonably hazardous for the patient. 8. Vitamin E supplementation for any reason ≤ 7 days prior to randomization. (Exception: one multivitamin per day that contains ≤ 100 IU \[mg\] of Vitamin E, will be permitted.) 9. Any of the following: pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception 10. Taking anticoagulant medication (i.e. coumadin, low molecular weight heparin (LMWH), or platelet aggregation inhibitors such as clopidgrel or aspirin) with the exception that 1 mg/day of coumadin for central line maintenance is allowed. 11. Diagnosed diabetes requiring insulin or oral hypoglycemic medications 12. Head or neck cancers 13. Scheduled to undergo radiation therapy while on study 14. History of hemorrhagic stroke 15. Patients receiving neo-adjuvant therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Chemotherapy-induced Sensory Peripheral Neuropathy ≥ Grade 2 | 6 months post completion of chemotherapy treatment | The chemotherapy-induced sensory peripheral neuropathy utilized the sensory neuropathy item from the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grading: Grade 0=none; grade 1=loss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function; grade 2=objective sensory alteration or paresthesia, including tingling, interfering with function, but not with activities of daily living; grade 3=sensory alteration or paresthesia interfering with activities of daily living; grade 4=permanent sensory losses that are disabling; and grade 5=death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Requiring Dose Reductions of Chemotherapy Due to Sensory Peripheral Neuropathy | 6 months post completion of chemotherapy treatment | — |
| Percentage of Patients Stopping Chemotherapy Before Treatment is Complete Due to Sensory Peripheral Neuropathy | 6 months post completion of chemotherapy treatment | — |
| Time to Onset of Sensory Peripheral Neuropathy ≥ Grade 2 | 6 months post completion of chemotherapy treatment | Time to onset of sensory peripheral neuropathy was calculated using incidences of the adverse event while the patient was receiving chemotherapy. |
| Duration of Sensory Peripheral Neuropathy ≥ Grade 2 | 6 months post completion of chemotherapy treatment | Duration of sensory peripheral neuropathy is the time from onset of grade 2+ neuropathy until the neuropathy is resolved to grade 1 or less during chemotherapy treatment. |
Countries
United States
Participant flow
Recruitment details
Two-hundred and seven (207) participants were recruited between December 2006 and December 2007 from 23 North Central Cancer Treatment Group (NCCTG) member sites.
Pre-assignment details
There were a total of 11 cancellations (4 Vitamin E, 7 Placebo), 1 major violation on Placebo and 7 ineligible (3 Vitamin E and 4 Placebo) participants. Of these, 18 participants of cancellations/ineligible were excluded from all analysis.
Participants by arm
| Arm | Count |
|---|---|
| Vitamin E Patients receive oral vitamin E twice daily beginning within 4 days of the start of chemotherapy course 1 and continuing until 1 month after completion of chemotherapy. | 96 |
| Placebo Patients receive oral placebo twice daily beginning within 4 days of the start of chemotherapy course 1 and continuing until 1 month after completion of chemotherapy. | 93 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 3 |
| Overall Study | Alternate Treatment | 2 | 4 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Other Medical Problems | 2 | 4 |
| Overall Study | Other Reasons | 6 | 3 |
| Overall Study | Withdrawal by Subject | 11 | 18 |
Baseline characteristics
| Characteristic | Total | Vitamin E | Placebo |
|---|---|---|---|
| Age, Customized <=50 years | 74 participants | 40 participants | 34 participants |
| Age, Customized >50 years | 115 participants | 56 participants | 59 participants |
| Planned number of chemotherapy cycles <=4 | 97 participants | 48 participants | 49 participants |
| Planned number of chemotherapy cycles >4 | 92 participants | 48 participants | 44 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 178 Participants | 91 Participants | 87 Participants |
| Region of Enrollment United States | 189 participants | 96 participants | 93 participants |
| Sex: Female, Male Female | 155 Participants | 80 Participants | 75 Participants |
| Sex: Female, Male Male | 34 Participants | 16 Participants | 18 Participants |
| Type of cancer Breast | 115 participants | 58 participants | 57 participants |
| Type of cancer Lung | 5 participants | 1 participants | 4 participants |
| Type of cancer Other Cancer | 69 participants | 37 participants | 32 participants |
| Type of chemotherapy Carboplatin | 2 participants | 1 participants | 1 participants |
| Type of chemotherapy Cisplatin | 8 participants | 4 participants | 4 participants |
| Type of chemotherapy Combination | 20 participants | 10 participants | 10 participants |
| Type of chemotherapy Oxaliplatin | 50 participants | 24 participants | 26 participants |
| Type of chemotherapy Taxane | 109 participants | 57 participants | 52 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 96 | 25 / 93 |
| serious Total, serious adverse events | 0 / 96 | 0 / 93 |
Outcome results
Primary
Percentage of Patients With Chemotherapy-induced Sensory Peripheral Neuropathy ≥ Grade 2
The chemotherapy-induced sensory peripheral neuropathy utilized the sensory neuropathy item from the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grading: Grade 0=none; grade 1=loss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function; grade 2=objective sensory alteration or paresthesia, including tingling, interfering with function, but not with activities of daily living; grade 3=sensory alteration or paresthesia interfering with activities of daily living; grade 4=permanent sensory losses that are disabling; and grade 5=death.
Time frame: 6 months post completion of chemotherapy treatment
Population: Participants who received at least one dose of assigned therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin E | Percentage of Patients With Chemotherapy-induced Sensory Peripheral Neuropathy ≥ Grade 2 | 34 percentage of participants |
| Placebo | Percentage of Patients With Chemotherapy-induced Sensory Peripheral Neuropathy ≥ Grade 2 | 29 percentage of participants |
p-value: 0.43Chi-squared
Secondary
Duration of Sensory Peripheral Neuropathy ≥ Grade 2
Duration of sensory peripheral neuropathy is the time from onset of grade 2+ neuropathy until the neuropathy is resolved to grade 1 or less during chemotherapy treatment.
Time frame: 6 months post completion of chemotherapy treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vitamin E | Duration of Sensory Peripheral Neuropathy ≥ Grade 2 | 36 days |
| Placebo | Duration of Sensory Peripheral Neuropathy ≥ Grade 2 | NA days |
Secondary
Percentage of Patients Requiring Dose Reductions of Chemotherapy Due to Sensory Peripheral Neuropathy
Time frame: 6 months post completion of chemotherapy treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin E | Percentage of Patients Requiring Dose Reductions of Chemotherapy Due to Sensory Peripheral Neuropathy | 3 percentage of patients |
| Placebo | Percentage of Patients Requiring Dose Reductions of Chemotherapy Due to Sensory Peripheral Neuropathy | 5 percentage of patients |
p-value: 0.49Fisher Exact
Secondary
Percentage of Patients Stopping Chemotherapy Before Treatment is Complete Due to Sensory Peripheral Neuropathy
Time frame: 6 months post completion of chemotherapy treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin E | Percentage of Patients Stopping Chemotherapy Before Treatment is Complete Due to Sensory Peripheral Neuropathy | 4 percentage of participants |
| Placebo | Percentage of Patients Stopping Chemotherapy Before Treatment is Complete Due to Sensory Peripheral Neuropathy | 3 percentage of participants |
p-value: 1Fisher Exact
Secondary
Time to Onset of Sensory Peripheral Neuropathy ≥ Grade 2
Time to onset of sensory peripheral neuropathy was calculated using incidences of the adverse event while the patient was receiving chemotherapy.
Time frame: 6 months post completion of chemotherapy treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vitamin E | Time to Onset of Sensory Peripheral Neuropathy ≥ Grade 2 | 58 days |
| Placebo | Time to Onset of Sensory Peripheral Neuropathy ≥ Grade 2 | 69 days |